19-7174608-A-G

Variant names:

• chr19-7174608-A-G
• rs2229435
• NM_000208.4:c.1098T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000208.4(INSR):​c.1098T>C​(p.Ser366Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,613,494 control chromosomes in the GnomAD database, including 173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (11 hom., cov: 31)
  • Exomes 𝑓: 0.014 (162 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.962
• Publications: 7 publications found

Genes affected

INSR (HGNC:6091): (insulin receptor) This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

INSR Gene-Disease associations (from GenCC):

• insulin-resistance syndrome type A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 19-7174608-A-G is Benign according to our data. Variant chr19-7174608-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.962 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00955 (1448/151628) while in subpopulation NFE AF = 0.0157 (1066/67884). AF 95% confidence interval is 0.0149. There are 11 homozygotes in GnomAd4. There are 685 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.1098T>C	p.Ser366Ser	synonymous	Exon 4 of 22	NP_000199.2
	INSR	NM_001079817.3		c.1098T>C	p.Ser366Ser	synonymous	Exon 4 of 21	NP_001073285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.1098T>C	p.Ser366Ser	synonymous	Exon 4 of 22	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.1098T>C	p.Ser366Ser	synonymous	Exon 4 of 21	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.1073T>C		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes AF: 0.00956 AC: 1448 AN: 151510 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00738

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00567

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.00961 AC: 2416 AN: 251406 AF XY: 0.00963

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.00945

GnomAD4 exome AF: 0.0139 AC: 20310 AN: 1461866 Hom.: 162 Cov.: 33 AF XY: 0.0136 AC XY: 9895 AN XY: 727236

African (AFR) AF: 0.00203 AC: 68 AN: 33480

American (AMR) AF: 0.00409 AC: 183 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00660 AC: 569 AN: 86258

European-Finnish (FIN) AF: 0.0128 AC: 686 AN: 53416

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.0163 AC: 18106 AN: 1111994

Other (OTH) AF: 0.0101 AC: 608 AN: 60392

GnomAD4 genome AF: 0.00955 AC: 1448 AN: 151628 Hom.: 11 Cov.: 31 AF XY: 0.00925 AC XY: 685 AN XY: 74064

African (AFR) AF: 0.00256 AC: 106 AN: 41368

American (AMR) AF: 0.00737 AC: 112 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00547 AC: 26 AN: 4754

European-Finnish (FIN) AF: 0.0111 AC: 117 AN: 10512

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0157 AC: 1066 AN: 67884

Other (OTH) AF: 0.00618 AC: 13 AN: 2104

Alfa AF: 0.00990 Hom.: 7

Bravo AF: 0.00807

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0137

EpiControl AF: 0.0134

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hyperinsulinism due to INSR deficiency (1)
-	-	1	Insulin-resistant diabetes mellitus AND acanthosis nigricans (1)
-	-	1	Leprechaunism syndrome (1)
-	-	1	not specified (1)
-	-	1	Rabson-Mendenhall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.9
DANN	Benign	0.51
PhyloP100		0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2229435; hg19: chr19-7174619; COSMIC: COSV100251262;